Lipoprotein lipase (EC 3.1.1.34) is an important enzyme in the metabolism of triglyceride-rich lipoproteins. It is synthesized in the parenchymal cells of adipose tissue and skeletal and cardiac muscle, where it is transferred to binding sites at the vascular side of endothelial cells on the vascular endothelium. Current understanding is that LPL plays an important role in the regulation of lipoprotein and lipid metabolism, as follows. The noncovalently-linked glycosylated homodimer is thought to be transported to the vascular endothelium, where it binds heparan sulphate proteoglycans at the luminal surface. Subsequent catabolism of triglycerides from both chylomicrons (CM) and very low density lipoproteins (VLDL) is understood to allow the uptake and utilization of the free fatty acids and glycerol for energy and storage in muscle and adipose tissue respectively. Chylomicron and VLDL remnants may either be used in high density lipoprotein (HDL) or low density lipoprotein (LDL) particle formation respectively, or taken up by the liver and repackaged into new VLDL particles. LPL has an obligatory requirement for its activator apolipoprotein (apo) CII, a small protein of 79 amino acids that is present on CM and VLDL particles. Inhibitors of LPL include free fatty acids, apo CIII, and possibly apo E. Another inhibitor is high concentrations of salt (1M NaCl).
Although the cellular origin of LPL in the circulation is unclear, and may represent an accumulation from several tissue sources, its primary site of action is understood to be at the luminal surface of the vascular endothelium. Due to its non-covalent interaction with heparan sulphate proteoglycans, LPL may be displaced into the plasma by an intravenous bolus injection of heparin. Thus, LPL activity and protein levels can be simply assessed by taking a small sample of post-heparin plasma (PHP). Aliquots of this PHP can then be used in either a synthetic, radiolabled triglyceride (TG) assay for lipolytic activity or be measured by LPL specific antibodies for protein levels. Lipid measures may be performed in pre-heparin samples since the release of LPL may cause rapid lipolysis of the triglyceride in the sample.
Complete LPL deficiency occurs in approximately 1 in 106 persons, and the frequency is much higher in the French Canadian population where it may occur in up to 1 in 5000 individuals. The clinical manifestations of complete LPL deficiency in humans stem from infancy with a failure to thrive, colicky abdominal pain, hepatosplenomegaly, chylomicronemia characterized by lactescent plasma, eruptive xanthomata, lipemia retinalis and life threatening pancreatitis. Lipid lowering drugs are ineffective and even rigid dietary restrictions are often poorly tolerated. The development of therapies for LPL deficiency would represent a major advance for persons suffering from this disorder.
Recently, patients with mutations in the LPL gene which result in partial defects in LPL catalytic function have been identified and, in fact, are very common in the general population. Collectively, known mutations resulting in partial catalytic defects in LPL are now estimated to occur with a frequency of between 5-7% in the general population. The clinical presentation may be quiescent, evident only by marginally elevated triglyceride levels in the non-stressed state, with profound hypertriglyceridemia triggered by factors such as normal pregnancy, obesity or diabetes. Postprandial metabolic studies have been performed on individuals heterozygous for mutations in the LPL gene, demonstrating an unmasking of the lipolytic defect after a fat challenge, resulting in prolonged post-prandial lipemia and significant disturbances in lipoprotein levels and composition. There is also evidence that specific mutations that alter, but do not abolish, LPL activity, such as Asn291Ser, Asp9Asn, exist commonly in the general population (Reymer et al., Nat. Genet. 1995, 10:28-33; Gagné et al., Arterioscl.Thromb. 1994, 14(8):1250-1257). The significance of this is not yet fully understood although they are implicated in atherosclerosis susceptibility. A mutation that introduces a termination codon at position 447 in place of a serine codon (Ser447Ter or S447X) has been associated with decreased TG and increased HDL-cholesterol levels (Hokanson, 1997, International Journal of Clinical and Laboratory Research 27, 24-34; Gagné et al., Arteriosci. Thromb. 1994, 14(8):1250-1257; Mattu et al., 1994, Arteriosclerosis and Thrombosis 14, 1090-1097; Kuivenhoven et al., 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17, 595-599; Groenemeijer et al., 1997, Circulation 95, 2628-2635; Fisher et al., 1997, Atherosclerosis 135, 145-159; U.S. Pat. No. 5,658,729; Groenemeijer et al., Circulation 1997, 95:2628-2635; Gagne et al., Clin. Genet. 1999, 55(6):450-454). Correspondingly, in most studies this mutation seems to confer protection against CAD. The mechanism(s) behind these effects are not known.